DESCRIPTION SECTION

DESCRIPTION

Nifedipine is a drug belonging to a class of pharmacological agents known as the calcium channel blockers. Nifedipine is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-, dimethyl ester, C 17H 18N 2O 6, and has the structural formula:

Nifedipine is a yellow crystalline substance, practically insoluble in water but soluble in ethanol. It has a molecular weight of 346.3. Nifedipine GITS (Gastrointestinal Therapeutic System) tablet is formulated as a once-a-day controlled-release tablet for oral administration designed to deliver 30, 60, or 90 mg of nifedipine.

Inert ingredients in the formulations are: cellulose acetate; ferric oxide; hypromellose; magnesium stearate; polyethylene glycol; polyethylene oxide; potassium chloride; povidone; sodium chloride; titanium dioxide; propylene glycol and black iron oxide.

The USP Dissolution Test is pending.

System Components and Performance

Nifedipine extended-release tablets are similar in appearance to a conventional tablet. It consists, however, of a semipermeable membrane surrounding an osmotically active drug core. The core itself is divided into two layers: an “active” layer containing the drug, and a “push” layer containing pharmacologically inert (but osmotically active) components. As water from the gastrointestinal tract enters the tablet, pressure increases in the osmotic layer and “pushes” against the drug layer, releasing drug through the precision laser-drilled tablet orifice in the active layer.

Nifedipine extended-release tablets are designed to provide nifedipine at an approximately constant rate over 24 hours. This controlled rate of drug delivery into the gastrointestinal lumen is independent of pH or gastrointestinal motility. Nifedipine extended-release tablets depend for its action on the existence of an osmotic gradient between the contents of the bi- layer core and fluid in the gastrointestinal tract. Drug delivery is essentially constant as long as the osmotic gradient remains constant, and then gradually falls to zero. Upon swallowing, the biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the feces as an insoluble shell.

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DOSAGE & ADMINISTRATION SECTION

DOSAGE & ADMINISTRATION

Dosage must be adjusted according to each patient’s needs. Therapy for either hypertension or angina should be initiated with 30 or 60 mg once daily. Nifedipine Extended-Release Tablets USP should be swallowed whole and should not be bitten or divided. In general, titration should proceed over a 7 to 14 day period so that the physician can fully assess the response to each dose level and monitor blood pressure before proceeding to higher doses. Since steady-state plasma levels are achieved on the second day of dosing, titration may proceed more rapidly, if symptoms so warrant, provided the patient is assessed frequently. Titration to doses above 120 mg are not recommended.

Angina patients controlled on nifedipine capsules alone or in combination with other antianginal medications may be safely switched to nifedipine extended- release tablets at the nearest equivalent total daily dose (e.g., 30 mg t.i.d. of nifedipine capsules may be changed to 90 mg once daily of nifedipine extended-release tablets). Subsequent titration to higher or lower doses may be necessary and should be initiated as clinically warranted. Experience with doses greater than 90 mg in patients with angina is limited. Therefore, doses greater than 90 mg should be used with caution and only when clinically warranted.

Avoid coadministration of nifedipine with grapefruit juice (seeCLINICAL PHARMACOLOGY andPRECAUTIONS: Other Interactions).

No “rebound effect” has been observed upon discontinuation of nifedipine extended-release tablets. However, if discontinuation of nifedipine is necessary, sound clinical practice suggests that the dosage should be decreased gradually with close physician supervision.

Care should be taken when dispensing nifedipine extended-release tablets to assure that the extended release dosage form has been prescribed.

Coadministration with Other Antianginal Drugs

Sublingual nitroglycerin may be taken as required for the control of acute manifestations of angina, particularly during nifedipine titration. See PRECAUTIONS, Drug Interactions, for information on coadministration of nifedipine with beta blockers or long-acting nitrates.

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PRECAUTIONS SECTION

PRECAUTIONS

General -Hypotension: Because nifedipine decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of nifedipine is suggested. Close observation is especially recommended for patients already taking medications that are known to lower blood pressure. (SeeWARNINGS)

Peripheral Edema: Mild to moderate peripheral edema occurs in a dose dependent manner with an incidence ranging from approximately 10% to about 30% at the highest dose studied (180 mg). It is a localized phenomenon thought to be associated with vasodilation of dependent arterioles and small blood vessels and not due to left ventricular dysfunction or generalized fluid retention. With patients whose angina or hypertension is complicated by congestive heart failure, care should be taken to differentiate this peripheral edema from the effects of increasing left ventricular dysfunction.

**Information for Patients:**Nifedipine extended-release tablets should be swallowed whole. Do not chew, divide or crush tablets. Do not be concerned if you occasionally notice in your stool something that looks like a tablet. In nifedipine extended-release tablets, the medication is contained within a nonabsorbable shell that has been specially designed to slowly release the drug for your body to absorb. When this process is completed, the empty tablet is eliminated from your body.

**Laboratory Tests:**Rare, usually transient, but occasionally significant elevations of enzymes such as alkaline phosphatase, CPK, LDH, SGOT and SGPT have been noted. The relationship to nifedipine therapy is uncertain in most cases, but probable in some. These laboratory abnormalities have rarely been associated with clinical symptoms; however, cholestasis with or without jaundice has been reported. A small (5.4%) increase in mean alkaline phosphatase was noted in patients treated with nifedipine extended-release tablets. This was an isolated finding not associated with clinical symptoms and it rarely resulted in values which fell outside the normal range. Rare instances of allergic hepatitis have been reported. In controlled studies, nifedipine extended-release tablets did not adversely affect serum uric acid, glucose, or cholesterol. Serum potassium was unchanged in patients receiving nifedipine extended-release tablets in the absence of concomitant diuretic therapy, and slightly decreased in patients receiving concomitant diuretics.

Nifedipine, like other calcium channel blockers, decreases platelet aggregation in vitro. Limited clinical studies have demonstrated a moderate but statistically significant decrease in platelet aggregation and an increase in bleeding time in some nifedipine patients. This is thought to be a function of inhibition of calcium transport across the platelet membrane. No clinical significance for these findings has been demonstrated.

Positive direct Coombs test with/without hemolytic anemia has been reported, but a causal relationship between nifedipine administration and positivity of this laboratory test, including hemolysis, could not be determined.

Although nifedipine has been used safely in patients with renal dysfunction and has been reported to exert a beneficial effect, in certain cases, rare, reversible elevations in BUN and serum creatinine have been reported in patients with preexisting chronic renal insufficiency. The relationship to nifedipine therapy is uncertain in most cases but probable in some.

Drug Interactions:Beta-adrenergic blocking agents: (SeeINDICATIONS AND USAGE andWARNINGS) Experience in over 1400 patients with nifedipine capsules in a noncomparative clinical trial has shown that concomitant administration of nifedipine and beta-blocking agents is usually well tolerated, but there have been occasional literature reports suggesting that the combination may increase the likelihood of congestive heart failure, severe hypotension, or exacerbation of angina.

Long-acting Nitrates: Nifedipine may be safely coadministered with nitrates, but there have been no controlled studies to evaluate the antianginal effectiveness of this combination.

Digitalis: Administration of nifedipine with digoxin increased digoxin levels in nine of twelve normal volunteers. The average increase was 45%. Another investigator found no increase in digoxin levels in thirteen patients with coronary artery disease. In an uncontrolled study of over two hundred patients with congestive heart failure during which digoxin blood levels were not measured, digitalis toxicity was not observed. Since there have been isolated reports of patients with elevated digoxin levels, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing nifedipine to avoid possible over- or under-digitalization.

Coumarin Anticoagulants: There have been rare reports of increased prothrombin time in patients taking coumarin anticoagulants to whom nifedipine was administered. However, the relationship to nifedipine therapy is uncertain.

Cimetidine: A study in six healthy volunteers has shown a significant increase in peak nifedipine plasma levels (80%) and area-under-the-curve (74%), after a one week course of cimetidine at 1000 mg per day and nifedipine at 40 mg per day. Ranitidine produced smaller, non-significant increases. The effect may be mediated by the known inhibition of cimetidine on hepatic cytochrome P-450, the enzyme system probably responsible for the first-pass metabolism of nifedipine. If nifedipine therapy is initiated in a patient currently receiving cimetidine, cautious titration is advised.

Nifedipine is metabolized by CYP3A4. Coadministration of nifedipine with phenytoin, an inducer of CYP3A4, lowers the systemic exposure to nifedipine by approximately 70%. Avoid coadministration of nifedipine with phenytoin or any known CYP3A4 inducer or consider an alternative antihypertensive therapy.

CYP3A inhibitors such as fluconazole, itraconazole, clarithromycin, erythromycin, nefazodone, fluoxetine, saquinavir, indinavir, and nelfinavir may result in increased exposure to nifedipine when coadministered. Careful monitoring and dose adjustment may be necessary; consider initiating nifedipine at the lowest dose available if given concomitantly with these medications.

Other Interactions:

Grapefruit Juice: Coadministration of nifedipine with grapefruit juice resulted in approximately a doubling in nifedipine AUC and C max with no change in half-life. The increased plasma concentrations most likely result from inhibition of CYP 3A4 related first-pass metabolism. Avoid ingestion of grapefruit and grapefruit juice should be avoided while taking nifedipine.

**Carcinogenesis, Mutagenesis, Impairment of Fertility:**Nifedipine was administered orally to rats for two years and was not shown to be carcinogenic. When given to rats prior to mating, nifedipine caused reduced fertility at a dose approximately 5 times the maximum recommended human dose. There is a literature report of reversible reduction in the ability of human sperm obtained from a limited number of infertile men taking recommended doses of nifedipine to bind to and fertilize an ovum in vitro. In vivo mutagenicity studies were negative.

**Pregnancy:**Pregnancy Category C: Nifedipine has been shown to produce teratogenic findings in rats and rabbits, including digital anomalies similar to those reported for phenytoin. Digital anomalies have been reported to occur with other members of the dihydropyridine class and are possibly a result of compromised uterine blood flow. Nifedipine administration was associated with a variety of embryotoxic, placentotoxic, and fetotoxic effects, including stunted fetuses (rats, mice, rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, rabbits), and prolonged pregnancy/decreased neonatal survival (rats; not evaluated in other species). On a mg/kg basis, all of the doses associated with the teratogenic embryotoxic or fetotoxic effects in animals were higher (5 to 50 times) than the maximum recommended human dose of 120 mg/day. On a mg/m 2 basis, some doses were higher and some were lower than the maximum recommended human dose, but all are within an order of magnitude of it. The doses associated with placentotoxic effects in monkeys were equivalent to or lower than the maximum recommended human dose on a mg/m 2 basis.

There are no adequate and well-controlled studies in pregnant women. Nifedipine extended-release tablets should be used during pregnancy only if the potential benefit justifies the potential risk.

**Lactation:**Nifedipine is transferred through breast milk. Nifedipine extended-release tablets should be used during breastfeeding only if the potential benefit justifies the potential risk.

**Pediatric Use:**Safety and effectiveness in pediatric patients have not been established.

Geriatric Use:Age appears to have a significant effect on the pharmacokinetics of nifedipine. The clearance is decreased resulting in a higher AUC in the elderly. These changes are not due to changes in renal function (seeCLINICAL****PHARMACOLOGY,Pharmacokinetics).

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ADVERSE REACTIONS SECTION

ADVERSE EXPERIENCES

Over 1000 patients from both controlled and open trials with nifedipine extended-release tablets in hypertension and angina were included in the evaluation of adverse experiences. All side effects reported during nifedipine extended-release tablets therapy were tabulated independent of their causal relation to medication. The most common side effect reported with nifedipine extended-release tablets was edema which was dose related and ranged in frequency from approximately 10% to about 30% at the highest dose studied (180 mg). Other common adverse experiences reported in placebo-controlled trials include:

Of these, only edema and headache were more common in nifedipine extended- release tablets patients than placebo patients.

The following adverse reactions occurred with an incidence of less than 3.0%. With the exception of leg cramps, the incidence of these side effects was similar to that of placebo alone.

Body as a Whole/Systemic: asthenia, flushing, pain

Cardiovascular: palpitations

Central Nervous System: insomnia, nervousness, paresthesia, somnolence

Dermatologic: pruritus, rash

Gastrointestinal: abdominal pain, diarrhea, dry mouth, dyspepsia, flatulence

Musculoskeletal: arthralgia, leg cramps

Respiratory: chest pain (nonspecific), dyspnea

Urogenital: impotence, polyuria

Other adverse reactions were reported sporadically with an incidence of 1.0% or less. These include:

Body as a Whole/Systemic: face edema, fever, hot flashes, malaise, periorbital edema, rigors

Cardiovascular: arrhythmia, hypotension, increased angina, tachycardia, syncope

Central Nervous System: anxiety, ataxia, decreased libido, depression, hypertonia, hypoesthesia, migraine, paroniria, tremor, vertigo

Dermatologic: alopecia, increased sweating, urticaria, purpura

Gastrointestinal: eructation, gastroesophageal reflux, gum hyperplasia, melena, vomiting, weight increase

Musculoskeletal: back pain, gout, myalgias

Respiratory: coughing, epistaxis, upper respiratory tract infection, respiratory disorder, sinusitis

Special Senses: abnormal lacrimation, abnormal vision, taste perversion, tinnitus

Urogenital/Reproductive: breast pain, dysuria, hematuria, nocturia

Adverse experiences which occurred in less than 1 in 1000 patients cannot be distinguished from concurrent disease states or medications.

The following adverse experiences, reported in less than 1% of patients, occurred under conditions (e.g., open trials, marketing experience) where a causal relationship is uncertain: gastrointestinal irritation, gastrointestinal bleeding, gynecomastia.

Gastrointestinal obstruction resulting in hospitalization and surgery, including the need for bezoar removal, has occurred in association with nifedipine extended-release tablets, even in patients with no prior history of gastrointestinal disease. (SeeWARNINGS)

Cases of tablet adherence to the gastrointestinal wall with ulceration have been reported, some requiring hospitalization and intervention.

In multiple-dose U.S. and foreign controlled studies with nifedipine capsules in which adverse reactions were reported spontaneously, adverse effects were frequent but generally not serious and rarely required discontinuation of therapy or dosage adjustment. Most were expected consequences of the vasodilator effects of nifedipine.

There is also a large uncontrolled experience in over 2100 patients in the United States. Most of the patients had vasospastic or resistant angina pectoris, and about half had concomitant treatment with beta-adrenergic blocking agents. The relatively common adverse events were similar in nature to those seen with nifedipine extended-release tablets.

In addition, more serious adverse events were observed, not readily distinguishable from the natural history of the disease in these patients. It remains possible, however, that some or many of these events were drug related. Myocardial infarction occurred in about 4% of patients and congestive heart failure or pulmonary edema in about 2%. Ventricular arrhythmias or conduction disturbances each occurred in fewer than 0.5% of patients.

In a subgroup of over 1000 patients receiving nifedipine with concomitant beta blocker therapy, the pattern and incidence of adverse experiences was not different from that of the entire group of nifedipine-treated patients. (See PRECAUTIONS)

In a subgroup of approximately 250 patients with a diagnosis of congestive heart failure as well as angina, dizziness or lightheadedness, peripheral edema, headache, or flushing each occurred in one in eight patients. Hypotension occurred in about one in 20 patients. Syncope occurred in approximately one patient in 250. Myocardial infarction or symptoms of congestive heart failure each occurred in about one patient in 15. Atrial or ventricular dysrhythmias each occurred in about one patient in 150.

In post-marketing experience, there have been rare reports of exfoliative dermatitis caused by nifedipine. There have been rare reports of exfoliative or bullous skin adverse events (such as erythema multiforme, Stevens-Johnson Syndrome, and toxic epidermal necrolysis) and photosensitivity reactions. Acute generalized exanthematous pustulosis also has been reported.

To report SUSPECTED ADVERSE REACTIONS, contact TWi Pharmaceuticals, Inc. at 1-844-518-2989 or FDA at 1-800-FDA-1088 orwww.fda.gov/medwatch.

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